Dosage form for time-varying patterns of drug delivery

ABSTRACT

A dosage form is disclosed that comprises means inside the dosage form for providing a substantially drug-free interval before the dosage form delivers a drug from inside the dosage form. The dosage form in an embodiment comprises a drug on the exterior of the dosage form, which drug is available for immediate delivery.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of Ser. No. 07,576,042, filed Aug. 31,1990, now U.S. Pat. No. 5,156,850.

This application is copending with an application Ser. No. 07/862,665.This applications is incorporated herein by reference and benefit isclaimed of their filing dates. These applications are assigned to theALZA Corporation of Palo Alto, Calif.

DESCRIPTION OF TECHNICAL FIELD

This invention pertains to a novel dosage form for time-varying patternsof drug delivery. More particularly, the invention concerns a dosageform provided as an osmotic device comprising means for therate-programmed delivery of a drug in time-varying patterns to a drugrecipient.

DESCRIPTION OF BACKGROUND ART

Presently, pharmacy and medicine provide delivery systems for theconstant-rate delivery of a drug to a drug-recipient user. The prior artprovides infusion pumps as disclosed by Perry, Carpenter and Griesengerin U.S. Pat. No. 4,318,400, oral matrix systems as disclosed by Urquhartand Theeuwes in U.S. Pat. No. 4,863,744, osmotic systems as patented byTheeuwes and Higuchi in U.S. Pat. Nos. 3,845,770 and 3,916,899,osmopolymer-powered systems as provided by Wong, Barclay, Deters andTheeuwes in U.S. Pat. No. 4,783,337, and implants as presented by Choiand Heller in U.S. Pat. No. 4,093,709, for constant-rate delivery of adrug of the longest duration consistent with reproducible therapeuticresults.

While these prior art delivery systems provide good therapy and achievetheir intended results there are however, some therapeutic programs thatrequire the dose of drug be administered in time-varying patterns ofdelivery. The time-varying patterns of drug delivery include (1) adrug-free interval followed by drug pulses of various duration forextended periods of time, (2) an immediate drug does followed by adrug-free interval followed by a drug-delivery period, and (3) a singledose followed by a delayed dose for optimum therapy, and like patternsof drug delivery.

For example, it is known, in Chronobiologia, Vol. 13, pages 239 to 243,(1986), that blood pressure has within-day rhythmicity, and that thehighest pressure values are seen often in the morning hours just afterwaking by the patient. The rise in blood pressure occurring at wakingrequires a dosage form that is administered on retiring and delivers itsdrug after a drug-free interval during sleep. This drug delivery patternprovides the need for therapy at the appropriate time, therebysubstantially lessening the incidence of a waking elevated bloodpressure. Presently a dosage form is unavailable to fulfill this need.It is self-evident from the above presentation that a critical andpresently unfilled need exists for a delivery system that can delivery adose of drug in a time-varying pattern of delivery. The need exits for aprogrammable delivery system that can provide a desired time-profile ofdrug administration to achieve the intended and therapeutic effect.

DISCLOSURE OF OBJECTS OF THE INVENTION

Accordingly, in the light of the above presentation, it is an immediateobject of this invention to provide a novel dosage form that overcomesthe shortcomings of the prior art and fully satisfies the critical andunfilled need for the dosage form.

Another primary object of this invention is to provide a dosage form fortime-varying patterns of drug delivery for achieving optimum therapy.

Another primary object of this invention is to provide a programmabledrug-delivery system that substantially fulfills the pressing need ofthe prior art and also represents an unexpected improvement in thedispensing art.

Another object of the present invention is to provide a programmabledrug-delivery system adapted as a dosage form for a rate-programmed drugdelivery at time-varying patterns.

Another object of the present invention is to provide a dosage formcomprising structural means for providing drug-free intervals followedby drug-delivery periods of various time durations.

Another object of the present invention is to provide a dosage that candeliver an instant-pulse dose of a therapeutic drug, followed by adelayed delivery of drug, and then deliver a dose of drug.

Another object of the present invention is to provide a dosage formcomprising two timed spaced-apart doses of drug in a single dosage form.

Another object of the invention is to provide a dosage form comprisingtwo doses of drug in a single dosage form that can be used for twice aday dosing of drug.

Another object of the present invention is to provide a novel dosageform manufactured in the form of a drug delivery device comprising meansfor delivering a pulsed dose of drug to a human, means for providing adrug-free interval, and then providing a recurring pulse dose of drug tothe human.

Another object of the invention is to make available a dosage form thatdelivers a first or instant dose of drug at bed-time for providing drugduring sleep, and a second or delayed drug early in the morning forproviding drug therapy on awakening from sleep.

Another object of the invention is to make available a dosage form thatdelivers a first dose of drug in the morning and a second dose of drugin the afternoon thereby providing two doses of drug therapy from asingle dosage form.

Another object of the invention is to provide a dosage form thatdelivers a drug in pulses to replace twice-a-day dosing of drug orthrice-a-day dosing of drug.

Other objects, features, and advantages of the invention will be moreapparent to those versed in the dispensing art from the followingspecification, taken in conjunction with the drawing figures and theaccompanying claims.

BRIEF DISCLOSURE OF THE DRAWING FIGURES

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a view of a dosage system provided by the invention, whichdosage form is designed, sized and adapted for admitting into abiological environment of use for time-varying patterns of drug deliveryincluding drug-free intervals between drug doses;

FIG. 2 is a view of the dosage system of FIG. 1, wherein FIG. 2 depictsa dose of drug on the exterior surfaces for administering a druginstantly in a short period of time to a recipient followed by adrug-free interval from the interior of the dosage system;

FIG. 3 is an opened view of FIG. 1 for illustrating the internalstructure of the dosage system for proving a time-interval, drug-freeperiod followed by a drug delivery period over time;

FIG. 4 is an opened view of FIG. 1 depicting a dosage form manufacturedas a programmable dosage form that provides time-varying patterns ofdrug delivery including drug-free intervals between drug doses ofvarious drug-release durations including instant drug delivery andprolonged drug delivery with the latter delivered through a multiplicityof exit passageways;

FIG. 5 is a graph that depicts the osmotic pressure in atmospheresdeveloped by a group of osmotic polymers;

FIGS. 6, 8 and 10 depict the release rate pattern in hours for deliverysystems provided by the invention; and,

FIGS. 7, 9, and 11 depict the cumulative amount released over aprolonged period of time by dosage forms provided by the invention.

In the drawing figures and in the specification, like parts in relatedfigures are identified by like numbers. The terms appearing earlier inthe specification, and in the description of the drawing figures, aswell as embodiments thereof, are further described elsewhere in thedisclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawings figures in detail, which drawing figures arean example of the dosage forms provided by the invention, and whichexamples are not to be construed as limiting, one example of the dosageform is illustrated in FIG. 1 and it is designed by the numeral 10. InFIG. 1, dosage form 10 comprises a body 11 comprising a wall 12 thatsurrounds and forms an internal compartment, not seen in FIG. 1. Dosageform 10 further comprises at least one exit means 13, or more than oneexit means 13 for connecting the interior of dosage form 10 withexterior of dosage form 10.

Dosage form 10, as seen in drawing FIG. 2, depicts one presentlypreferred optional embodiment of the invention, that comprises anexternal coat 14 on the exterior surface of wall 12. Coat 14 is acomposition comprising 1 mg to 200 mg of drug 15, represented by dots.Exterior coat 14 provides instant drug 15 according to the programmabledelivery patterns provided by dosage form 10. Drug 15 is blended with anaqueous soluble film-forming carrier such as methyl- cellulose,hydroxypropylcellulose, hydroxypropylmethyl- cellulose, optionallyblended with a plasticizer such as polyethylene glycol or acetylatedtriglycerides or the like. Coat 14 provides instant drug therapy, asfilm coat 14 dissolves or undergoes dissolution in the presence of fluidand concurrently therewith delivers drug 15 to drug receptor. Coat 14comprising drug 15 provides (1) instant drug followed by a drug-freeinterval, and (2) it essentially overcomes the time required for drug 15to be delivered from the interior of dosage form 10. A start-up time isneeded for dosage form 10 to imbibe exterior fluid through wall 12 fordosage form 10 to hydrodynamically dispense drug through exit means 13.

Dosage form 10, as provided by this invention, and as seen in the abovedrawing figures can be manufactured for administering a drug 15 by theoral route, and in another embodiment, dosage form 10 comprisingexterior drug 15 can be sized and shaped for administering drug 15 bythe sublingual and buccal routes. The sublingual and buccal routes canbe used for quicker therapy and they can be used when a smaller dose ofdrug is needed for therapy. The buccal and sublingual routes can be usedas a by-pass of the first pass of hepatic metabolism of drug 15. Thesublingual or buccal routes can be used for administering the firstpulse of drug, followed by permitting dosage form 10 to enter thestomach for subsequent drug delivery.

In drawing FIG. 3, dosage form 10 is manufactured as an osmotic device,and it is seen in opened view at 16. In drawing FIG. 3, dosage form 10comprises body 11, wall 12, that is sectioned at 16, and which wall 12surrounds and delivers an internal compartment 17. Wall 12 comprises atleast one exit means 13 that connects compartment 17 with the exteriorof dosage form 10. Dosage form 10 can comprise more than one exit means13, as presented later in the specification.

Wall 12 of dosage form 10, comprises totally, or in at least a part, acomposition that is permeable to the passage of an exterior fluidpresent in the environment of use. Wall 12 is substantially impermeableto the passage of drug and other optional ingredients that may bepresent in compartment 17. The semipermeable wall 12 is substantiallyinert, that is, it maintains its physical and chemical integrity duringthe dispensing of a drug from dosage form 10. Wall 12 in a presentlypreferred embodiment is formed totally or in at least a part of a memberselected from the group consisting of a cellulose ether, celluloseester, cellulose ester-ether. The cellulosic polymers have a degree ofsubstitution, D.S., on the anhydroglucose unit, from greater than 0 upto 3 inclusive. By degree of substitution is meant the average number ofhydroxyl groups originally present on the anhydroglucose unit comprisingthe cellulosepolymer that are replaced by a substituting group.Representative materials include a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetiracylate, cellulose acetate, cellulose diacetate, cellulosetiracetate, mon, di and tricellulose alkanylates, mono, di andtricellulose aroylates, and the like. Exemplary polymers includecellulose acetate having a D.S. up to 1 and an acetyl content up to 21%;cellulose acetate having an acetyl content of 32 to 39.8%; celluloseacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%;cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 35 to44.8%, and the like. More specific cellulosic polymers include cellulosepropionate having a D.S. of 1.8 and a propyl content of 39.2 to 45% anda hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having aD.S. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%,a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%;cellulose triacylates having a D.S of 2.9 to 3 such as cellulosetriacetate, cellulose trivalerate, cellulose trilaurate, cellulosetripalmitate, cellulose trisuccinate, and cellulose trioctanoate;cellulose diacylates having a D.S. of 2.2 to 2.6 such as cellulosedisuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulosedipentanoate, co-esters of cellulose such as cellulose acetate butyrateand cellulose acetate propionate, and the like.

Additional semipermeable wall forming polymers include acetaldehydedimethyl cellulose acetate, cellulose acetate ethyl carbamate, celluloseacetate methyl carbamate, cellulose acetate dimethyl aminoacetate,semipermeable polyamides; semipermeable polyurethanes; semipermeablesulfonated polystyrenes; semipermeable cross-linked selectivelypermeable polymers formed by the coprecipitation of a polyanion and apolycation as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;3,541,005; 3,541,006and 3,546,142; semipermeable polymers as disclosedby Loeb and Sourirajan in U.S. Pat. No. 3,133,132; semipermeable lightlycross-linked polystyrene derivatives; semipermeable cross-linkedpoly(sodium styrene sulfonate); and semipermeable cross-linkedpoly-(vinylbenzyltrimethyl ammonium chloride). The polymers are known tothe art in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020; and inHandbook of Common Polymers by Scott, J. R. and Roff, W. J., 1971,published by CRC Press, Cleveland, Ohio. In another embodiment, wall 12of dosage form 10 of drawing FIG. 3 optionally comprises from 0 weightpercent (wt. %) to 30 wt. % of a member selected from the groupconsisting of a cellulose ether selected from the group consisting of ahydroxypropylcellulose and a hydroxypropylmethylcellulose, and from 0wt. % to 30 wt. % of a poly- ethylene glycol. The total weight of allcomponents comprising wall 12 is equal to 100 wt. %.

Dosage form 10 of drawing FIG. 3, comprises a first composition or firstlayer 18, positioned in compartment 17 next to passageway 13. Layer 18is drug-free. Layer 18 provides a drug-free period before a drug isdelivered from compartment 17, or layer 18 provides a drug-free intervalbetween drug 15 delivered from outside coat 14 and drug delivered frominside compartment 17. First layer 18 comprises a member selected fromthe group consisting of an osmagent 19, represented by V, and anosmopolymer 20, represented by squares. First layer 18 optionallycomprises a binder 21 represented by wavy lines.

The term osmagent 19, as used herein, also includes osmoticallyeffective solute, osmotically effective compounds, and osmotic agent.The osmotically effective compounds that can be used for the purpose ofthis invention include inorganic and organic compounds that exhibit anosmotic pressure gradient across wall 12 against an external fluid.Osmotically effective compounds useful for the present purpose includemagnesium sulfate, magnesium chloride, sodium chloride, lithiumchloride, potassium sulfate, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, calcium bicarbonate, sodium sulfate,calcium sulfate, potassium acid phosphate, calcium lactate, d-mannitol,urea, inositol, magnesium succinate, tartaric acid, carbohydrates suchas raffinose, sucrose, glucose, α-d-lactose monohydrate, and mixturesthereof. The compound is initially present in first layer 18 in excessand it can be in any physical form such as particle, crystal, pellet,tablet, strip, ground, pulverized, film, or granule. The osmoticpressure of saturated solutions of various osmotically effectivecompounds and for mixtures of osmotic compounds at 37° C., in water, islisted in Table 1. In the table, the osmotic pressure π, is inatmospheres, ATM. The osmotic pressure is measured in a commerciallyavailable osmometer that measured the vapor pressures difference betweenpure water and the solution to be analyzed, and according to standardthermodynamic principles, the vapor pressure difference is convertedinto osmotic pressure. In Table 1, osmotic pressures of from 20 ATM to500 ATM are set forth; of course, the invention includes the use oflower osmotic pressures from zero, and higher osmotic pressures thanthose set forth by way of example in Table 1. The osmometer used for thepresent measurements is identified as Model 302B, Vapor PressureOsmometer, manufactured by the Hewlett Packard Co., Avondale, Pa.

                  TABLE I                                                         ______________________________________                                                             OSMOTIC                                                  COMPOUND OR MIXTURE  PRESSURE ATM                                             ______________________________________                                        Lactose-Fructose     500                                                      Dextrose-Fructose    450                                                      Sucrose-Fructose     430                                                      Mannitol-Fructose    415                                                      Sodium Chloride      356                                                      Fructose             355                                                      Lactose-Sucrose      250                                                      Potassium Chloride   245                                                      Lactose-Dextrose     225                                                      Mannitol-Dextrose    225                                                      Dextrose-Sucrose     190                                                      Mannitol-Sucrose     170                                                      Sucrose              150                                                      Mannitol-Lactose     130                                                      Dextrose              82                                                      Potassium Sulfate     39                                                      Mannitol              38                                                      Sodium Phosphate Tribasic - 12H.sub.2 O                                                             36                                                      Sodium Phosphate Dibasic - 7H.sub.2 O                                                               31                                                      Sodium Phosphate Dibasic - 12H.sub.2 O                                                              31                                                      Sodium Phosphate Dibasic - Anhydrous                                                                29                                                      Sodium Phosphate Monobasic - H.sub.2 O                                                              28                                                      ______________________________________                                    

In another technique, the osmotic pressure is measured using a porouscell impregnated with copper ferrocyanide filled with water and immersedin a vessel containing the aqueous solution. The pressure is measured bymeans of an attached manometer. The system is allowed to stand untilthere is no further increase in pressure. Then the osmotic pressure isjust balanced by the hydrostatic pressure in the column of solution. Apressure up to several hundred atmospheres can be measured by using acapillary manometer for the pressure measurement. Other methods that canbe used for measuring osmotic pressure include using this apparatus andapplying a pressure to the solution sufficient to balance an osmoticpressure read in a pressure gauge. Calculations of pressure can be madealso from changes in the refractive index of water on compression, andfrom the application of piezoelectric gauges. The techniques formeasuring osmotic pressure are disclosed in Physical Chemistry by WalterJ. Moore, Third Edition, pages 136 to 137, (1962) published byPrentice-Hall, Inc., Englewood Cliffs, N.J.

For the purpose of this invention, the solubility of osmagent or drug 15in a fluid can be determined by various art known techniques. One methodconsists in preparing a saturated solution of means 19 or of drug 15 forexample, a fluid plus the means or the drug and ascertaining by analysisthe amount of means or drug present in a definite quality of the fluid.A simple apparatus for this purpose consists of a test tube of mediumsize fastened upright in a water bath maintained at constant temperatureand pressure, for example 37.5° C. and one atmosphere. The fluid andmeans or drug are placed in the tube and stirred by means of a motordriven rotating glass spiral. After a given period of stirring, adefinite weight of the fluid is analyzed and the stirring continued foran additional period of time. If the analysis shows no increase aftersuccessive periods of stirring, in the presence of excess solid means ordrug in the fluid, the solution is saturated and the results are takenas the solubility of the means or drug in the fluid. Numerous othermethods are available for the determination of the solubility of themeans or the drug in a fluid. Typical methods used for the measurementof solubility are chemical analysis, measurement of density, refractiveindex, electrical conductivity, and the like. Details of the variousmethods for determining solubilities are described in United StatesPublic Health Service Bulletin, No. 67 of the Hygienic Laboratory;Encyclopedia of Science and Technology, Vol. 12, pages 542 to 556,1971McGraw-Hill, Inc., "Encyclopaedic Dictionary of Physics, Vol. 6,pages 545 to 557, 1962, Pergamon Press Inc.; and the like.

The osmopolymers 20 acceptable for forming first layer 18 comprisehydrophilic polymers that are noncross-linked, or lightly cross-linked,such as with cross-links formed by ionic, hydrogen, or covalent bonds.The osmopolymers 20, for the purpose of this invention, interact withwater and aqueous biological fluids and form a solution or a suspensionwith a high osmotic pressure that are osmotically pumped through exitmeans 13. The osmopolymers can be of plant and animal origin, preparedby modifying naturally occurring structures, and synthetic polymerosmopolymers. Hydrophilic polymeric materials for the purpose includepoly(hydroxyalkyl methacrylate), poly(N-vinyl-2-pyrrolidone), anionicand cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol)having a low acetate residual and cross-linked with glyoxal,formaldehyde, or glutaraldehyde, methyl cellulose cross-linked withdialdehyde, a mixture of cross-linked agar and carboxymethyl cellulose,a water soluble, water-swellable copolymer produced by forming adispersion of finely divided copolymer of maleic anhydride with styrene,ethylene, propylene, butylene, or isobutylene cross-linked with from0.001 to about 0.5 moles of a polyunsaturated cross-linking agent permole of maleic anhydride in the copolymer, water-swellable polymers ofN-vinyl lactams, cross-linked polyethylene oxides, and the like.

Other osmopolymers include osmopolymers exhibiting a cross-linking of0.05 to 60%, hydrophilic hydrogels known as Carbopol® acidic carboxypolymer, Cyanamer® polyacrylamides, cross-linked water-swellable indenemaleic anhydride polymers, Good-rite® polyacrylic Aqua-Keeps® acrylatepolymer, diester cross-linked polyglucan, and the like. The osmopolymersare known to the prior art in U.S. Pat. No. 3,865,108 issued to Hartop;in U.S. Pat. No. 4,002,173 issued to Manning; in U.S. Pat. No. 4,207,893issued to Michaels; and in Handbook of Common Polymersby Scott and Roff,published by the Chemical Rubber Company, Cleveland, Ohio.

Other osmopolymers that can be used for providing first layer includeagarose, alginates, amylopectin, arabinoglactan, carrageen, eucheuma,fucoidan, furcellaran, gelatin, guar gum, gum agar, gum arabic, gumghatti, gum karaya, gum tragacanth, hypnea, laminarin, locust bean gum,pectin, polyvinyl alcohol, polyvinyl pyrrolidone, propylene glycolaginates, n-vinyl lactam polysaccharides, xanthan gum, and the like. Theosmopolymers are known in Controlled Release System, FabricationTechnology, Vol. II, pg 46(1988), published by CRC Press, Inc.

The osmotic pressure of a hydrophilic polymer, an osmopolymer, or of anosmopolymer osmagent composition, can be measured by those versed in theart by measuring the increase in volume and weight of a compositioncomprising an osmopolymer, or an osmagent. The measurements are made byplacing a composition inside a cup comprising a semipermeable wall thatsurrounds a salt layer and an inner, fluid impermeable membrane, whichhas been immersed at 37° C. in water. The osmotic pressure of thecomposition is determined from the weight gain of the cup compared to asimilar cup filled with a saturated solution comprising an osmagent,such as sodium chloride, containing excess osmagent. Since, the osmoticpressure of the osmagent solution is known, the osmotic pressure of theosmopolymer is calculated therefrom.

The osmotic pressure generated from an osmotically active solution canbe ascertained by the simplified form of Van't Hoff's Law expressed asby equation 1: ##EQU1## wherein π is the osmotic pressure generated byan osmotic solute, R is the gas constant, T is the temperature (°K), C₂is the osmotic solute concentration in solution (mg/ml), MW₂ is themolecular weight of the solute, and i is the number of ionizable speciesor sites per molecule, for small molecules in which the solubility S ofthe compound can be calculated by substituting C=S, as seen fromaccompanying equation 2: ##EQU2##

For hydrophilic polymers which are usually miscible with water, then,the osmotic potential preferably is measured by water imbibition, inwhich the weight gain of the polymer is contained inside thesemipermeable cup described above. The osmotic pressure of theosmopolymer at any degree of water hydration is calculated from theknown water permeability of the semipermeable cup according to equation3: ##EQU3## wherein (dv/dt) is the water imbibition rate, h is themembrane thickness, A is the membrane area, and K is the waterpermeability of the membrane.

Accompanying FIG. 5 shows the osmotic profile for some osmopolymers. Theosmotic potential, according to Equation 1, is proportional to theionizable group in the polymer chain. If one assumes C₂ is about thesame for all miscible polymers, then the ionizable density (i/MW₂) isthe determining factor in the osmotic potential for differenthydrophilic polymers. In FIG. 5, the line with circles denotes apolyethylene oxide comprising a 5,000,000 molecular weight, the lineconnected with x indicates sodium carboxymethylcellulose wherein Hdenotes high viscosity and F denotes food grade cellulose (NaCMC.7HF),the line connected with triangles denotes hydroxypropylmethylcellulose,the line connected with squares denotes hydroxypropylcellulose, and theline connected through diamonds denotes starch. Accompanying Table IIcompares the i/MW₂ values for a group of osmopolymers, depicting thatthe larger the ionizable density for a polymer, the higher is itsosmotic potential which follows the same relative parameters as seen inFIG. 5. In FIG. 5, the hydration coefficient is the ratio (W_(H) /W_(P))wherein W_(H) is the weight of water imbibed into the osmopolymer andW_(P) is the weight of the dry osmopolymer. In FIG. 5, the work Klucel®EF denotes hydroxypropycellulose, and Plyox® Coagulant denotespolyethylene oxide comprising a 5,000,000 molecular weight.

                  TABLE II                                                        ______________________________________                                        Physical Chemical Properties of Osmopolymers                                                       m.v. of    ionizable density                             Polymer        i     Repeat Unit                                                                              i/m.v..sub.2 (× 10.sub.2)               ______________________________________                                        Sorbitol       6     182        3.3                                           Polyethylene oxide                                                                           1      44        2.27                                          Sodium carboxy-                                                                              2      94        2.13                                          vinylpolymer                                                                  Potassium      2     110        1.82                                          carboxyvinylpolymer                                                           Carboxyvinylpolymer                                                                          1      72        1.39                                          Pectin         1     .sup.˜ 200.sup.                                                                    0.50                                          Hydroxypropylmethyl                                                                          1     201        0.50                                          cellulose                                                                     Hydroxypropylcellulose                                                                       1      336*      0.30                                          ______________________________________                                         *When Molar Substitution equals 3.0                                      

The first layer 18 generally exhibits a viscosity of about 100centipoises to 10,000,000 centipoises, when dosage form 10 is in use atan animal temperature of 35° C. to 45° C. For example, first layer 18can comprise a polyethylene oxide with a molecular weight of 10,000 to7,000,000, for a 1% solution, the viscosity is generally between 5 to20,000 centipoises at a room temperature of 23° C.; for a first layer 18comprising a polyvinyl pyrrolidone with a molecular weight of between10,000 to 5,00,000, for a 10% solution, the viscosity is generallybetween 5 to 5000 centipoises at 25° C.; for ahydroxypropylmethylcellulose having a molecular weight of between 9,000to 241,000, a 2% solution in an aqueous media, the viscosity is about 3centipoises ubbelohde viscosity at 20° C. to 100,000 centipoisesubbelohde viscosity at 20° C. The viscosity of the first layer, or theviscosity of other compositions is ascertained by conventionalmeasurements. The viscosity, or the resistance that a composition offersto flow when it is subjected to a shear stress can be measured with aWells-Brookfield Viscometer. Methods on apparatus for measuringviscosity are known in Pharmaceutical Sciences, by Remington, 14th Ed.,pp. 359-71, (1970), published by Mack Publishing Co., Easton, Pa.

Dosage form 10, as seen in FIG. 3, comprises a second or drug layer 22.Drug layer 22 comprises a drug 15, represented by dots. The term "drug"as used herein, includes any physiologically or pharmacologically activesubstance that produces a local or systemic effect in animals, includingwarm blooded mammals; humans and primates; avians; household, sport andfarm animals; laboratory animals; fishes; reptiles and zoo animals. Theterm "physiologically" as used herein, denotes the administration of adrug to produce generally normal levels and functions. The term"pharmacologically", as used herein, denotes generally variations inresponse to the amount of drug administered to the host. See Stedman'sMedical Dictionary, 1966published by Williams and Wilkins, Baltimore,Md.

The active drug 15 that can be delivered includes inorganic and organiccompounds without limitation, including drugs that act on the peripheralnerves, adrenergic receptors, cholinergic receptors, nervous system,skeletal muscles, cardiovascular system, smooth muscles, bloodcirculatory system, synaptic sites, neuroeffector junctional sites,endocrine system, hormone systems, immunological system, reproductivesystem, skeletal system, autacoid systems, alimentary and excretorysystems, inhibitory of autocoid systems, alimentary and excretorysystems, inhibitory of autocoids and histamine systems. The active drugthat can be delivered for acting on these recipients includeanticonvulsants, analgesics, anti-Parkinsons, anti-inflammatories,calcium antagonists, anesthetics, antimicrobials, antimalarials,antiparasites, antihypertensives, antihistamines, antipyretics,alpha-adrenergic agonist, alpha-blockers, biocides, bactericides,bronchial dilators, beta-adrenergic blocking drugs, contraceptives,darciovascular drugs, calcium channel inhibitors, depressants,diagnostics, diuretics, electrolytes, hypnotics, hormonals,hyperglycemics, muscle contractants, muscle relaxants, ophthalmics,psychic energizers, parasympathomimetics, sedatives, sympathomimetics,tranquilizers, urinary tract drugs, vaginal drugs, vitamins,nonsteroidal anti-inflammatory drug, angiotensin converting enzymes,polypeptide drugs, and the like.

Exemplary drugs 15 are very soluble in water and can be delivered bydosage form 10 of this invention include prochlorperazine edisylate,ferrous sulfate, aminocaproic acid, potassium chloride, mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,benzphetamine hydrochloride, isoproterenol sulfate, methamphetaminehydrochloride, phenmetrazine hydrochloride, bethanechol chloride,methacholine chloride, pilocarpine hydrochloride, atropine sulfate,scopolamine bromide, isopropamide iodide, trihexethyl chloride,phenformin hydrochloride, methylphenidate hydrochloride, cimetidinehydrochloride, theophylline cholinate, cephalexin hydrochloride, and thelike.

Exemplary drug 15 poorly soluble in water and that can be delivered bydosage form 15 of this invention include diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperazine maleate, anisindione, diphenadione erythrityltetranitrate, digoxin, isofulrophate, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinal, aluminum aspirin, methotrexate, acetylsulfisoxazole, erhtyromycin, progestins, estrogenic, progestational,corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, triamcinolone, methylesterone, 17 beta-estradiol, ethinylestradiol, ethinyl estradiol 3-methyl ether, prednisolone, 17beta-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiderone, progesterone,norgesterone, norethynodrel, and the like.

Example of other drugs 15 that can be delivered by dosage form 10include aspirin, indomethacin, naproxen, fenoprofen, sulindac,indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol,atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa,chloropromaxine, methyldopa, dihydroxyphenylalanine, pivaloxyethyl esterof alpha-methyldopa hydrochloride, theophylline, calcium gluconate,ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac,ferrous lactate, vincamine, verapamil, midazolam, diazepam,phenoxybenzamine, diltiazem, milrinone, mandol, guanabenz,hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen,tolmetin, alclofenac, mefenamic, flufenamic, diflunisal, minodipine,nitredipine, nisoldipine nicardipine, felodipine, lidoflazine, tiapamil,gallopamil, amlodipine, mioflazine, lisinopril, analapril, captopril,ramipril,, endlapriat, famotidine, nizatidine, sucralfate, etintidine,tertatolol, minoxidil, chlordiazepoxide, chlordiazepoxide,hydrochloride, amintriptylin hydrochloride, imipramine hydrochloride,imipramine pamoate, and the like.

The term drug 15 as used for the purpose of this invention also embracesdrugs that are administered in the colon to produce a therapeuticeffect. The drugs include the drugs conventionally used in the treatmentof colitis, ulcerative colitis, Crohn's disease, idiopathic prototis andother disease of the colon. Representative drugs includesalicylazosulfapyridine, also known as sulfasalazine, and salazopyrin;adrenocorticosteroids, such as hydrocortisone, prednisolone phosphate,prednisolone sulfate, prednisone, prednisolone metasulphobenzoatesodium, prednisolone sodium phosphate and the like; corticosteroids suchas beclomethasone, beclomethasone acetate, beclomethasone valerate,beclomethasone propionate, beclomethasone diproprionate, and the like;cyclosporin; and the like. In another aspect, drug 15 also includesdrugs for treatment of irritable bowel syndrome, or drug 15 alters bowlmotility and fluid absorption, such drugs are represented by calciumchannel blocking drugs, opiads, anticholinergics and benzodiazepides.

Representative of drug 15 also include the non-steroidalanti-inflammatory, analgesic drugs, The non-steroidal anti-inflammatory,analgesic drugs include a member selected from the group consisting ofnonsteroidal propionic acid derivatives, nonsteroidal acetic acidderivatives, nonsteroidal fenamic acid derivatives, nonsteroidalbiphehylcarboxylic acid derivatives, and nonsteroidal axicamderivatives. The propionic acid derivatives include a member selectedfrom the group consisting of benoxaprofen, carprofen, flurbiprofen,fenoprofen, fenbufen, ibuprofen, indoprofen, ketoprofen, naproxen,miroprofen, oxaprozin, pranoprofen, pirprofen, suprofen, tiaprofenicacid, fluprofen, alminoprofen, bucloxic acid and the like. The aceticacid derivatives include a member selected from the group consisting ofalclofenac acematacin, aspirin, diclofenac, indomethacin, ibufenac,isoxepac, furofenac, fentiazac, clidanac, oxpinac, sluinda, tolmetin,zomepirac, zidometacin, tenclofenac, tiopinac, and the like. The fenamicacid nonsteroid drugs include mefenamic acid, fufenamic acid, niflumicacid, meclofenamic acid, tolfenamic acid, the like. Representativebiphenylcarboxylic carboxylic acid nonsteroid drugs include diflunisal,flufenisal, and the like. Representative nonsteroidal oxicam drugsinclude isoxicam, piroxicam, sudoxicam, and the like. Other drugsinclude potassium chloride, potassium carbonate, and the like.

The drug 15 can be in second layer 22 in various forms, such asuncharged molecules, molecular complexes, pharmacologically acceptablesalts such as hydrochloride, hydrobromide, sulfate, laurate, palmitate,phosphate, nitrite, borate, acetate, maleate, tartrate, oleate andsalicylate. For acidic drugs, salts of metals, amines or organiccations; for example, quaternary ammonium can be used. Derivatives ofdrugs such as ester, ethers and amides can be used. Also, a drug that iswater insoluble can be used in a form that is water soluble derivativethereof to serve as a solute, and on its release from the device, isconverted by enzymes, hydrolyzed by body pH or other metabolic processesto the original biologically active form. The amount of beneficial drug15 in dosage form 10 is generally about from 0.05 ng to 5 g or more,with individual devices continuing, for example, 25 ng, 1 mg, 5 mg, 10mg, 25 mg, 125 mg, 500 mg, 750 mg, 1.0 g, 1.2 g, 1.5 g, and the like.The dosage form 10 can be administered once, twice or thrice daily. Thetherapeutically acceptable drugs are known to the art in PharmaceuticalSciences, 14th Ed., edited by Remington, (1979) published by MackPublishing Co., Easton, Pa.; The Drug, The Nurse, The Patient, IncludingCurrent Drug Handbook by Falconer, et al., (1974-1976) published bySaunder Company, Philadelphia, Pa.; Medicinal Chemistry, 3rd Ed., Vol. 1and 2, by Burger, published by Wiley-Interscience, New York; and inPhysician's Desk Reference, 38 Ed., (1984) published by MedicalEconomics Co., Oradell, N.J.

Drug 15 is present in second layer 22 with a composition or layerforming ingredient 23, identified by dashes 23. The composition formingingredients comprise a polymeric carrier selected from the groupconsisting of a water soluble gum such as carrageenan, fucoidan, gumghatti, tragacanthin, arabinoglactin, pectin, xanthan, and the like;water soluble salts of polysaccharides such as sodium alginate, sodiumtragacanthin, hydroxyalkylcellulose wherein the alkyl member is straightor branched of 1 to 7 carbons such as hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, and the like; syntheticwater-soluble cellulose-based layer formers such as methyl cellulose andit hydroxyalkyl methylcellulose derivatives such as a member selectedfrom the group consisting of hydroxyethyl methylcellulose, hydroxypropylmethylcellulose, hydroxybutyl methylcellulose, polyoxyethylenecomprising a molecular weight of 50,000 to 8,000,000 usually at apolyoxyethylene concentration up to 25 wt. %, and the like; and othercellulose polymers such as carboxymethylcellulose.

Second layer 22 can comprise other layer formers such as polyvinylpyrrolidone, a blend of gelatin and polyvinyl pyrrolidone, glucose, zincpalmitate, aluminum stearate, amgnesium oleate, pulverized teflon,halogenated vegetable oil, pulverized talc, and the like. Second layer22 comprises 0 weight percent to 95 weight percent of a polymericcarrier. Second layer 22 comprises 0 wt. % to 5 wt. % of a lubricantsuch as magnesium stearate, corn starch, potato starch, bentonite,citrus pulp, calcium stearate, stearic acid, and the like. Second layer22 optionally comprises 0 wt. % to 15 wt. % of a polyethylene glycol asa solubilizing agent and as a lubricant. Second layer 22 optionallycomprises from 0 wt. % to 20 wt. % of an osmagent such as a memberselected form the group consisting of magnesium sulfate, magnesiumchloride, potassium sulfate, sodium sulfate, sodium chloride, potassiumchloride, and the like. The osmagent in second layer 22 imbibes fluidinto the layer for enhancing its dispensing from dosage form 10. Theamount of all ingredients in second layer 22 is equal to 100 wt. %.

Dosage form 10 comprises a third layer 24 or push layer. The push thirdlayer 24 comprises an osmopolymer suitable for forming the third osmoticpush layer 24. The third layer comprises an osmopolymer that exhibitsfluid imbibition properties. The osmopolymers are swellable, hydrophilicpolymers which osmopolymers interact with water and aqueous biologicalfluids and swell or expand to an equilibrium state. The osmopolymersexhibit the ability to swell in water and retain a significant portionof the imbibed water within the polymer structure. The osmopolymersswell or expand to a very high degree, usually exhibiting a 2 to 60 foldvolume increase. The osmopolymers can be noncross-linked orcross-linked. The swellable, hydrophilic polymers are in one presentlypreferred embodiment lightly cross-linked, such cross-links being formedby covalent ionic bonds or residue crystalline regions after swelling.The osmopolymers can be of plant, animal or synthetic origin. Theosmopolymers are hydrophilic polymers. Hydrophilic polymers suitable forthe present purpose include poly(hydroxy-alkyl methacrylate) having amolecular weight of from 30,000 to 5,000,000; poly(vinyl-pyrrolidone)having molecular weight of from 10,000 to 360,000; anionic and cationichydrogels; polyelectrolyte complexes; poly(vinyl alcohol) having a lowacetate residual, cross-linked with glyoxal, formaldehyde, orglutaraldehyde and having a degree of polymerization from 200 to 30,000;a mixture of methyl cellulose, cross-linked agar and carboxymethylcellulose; a mixture of hydroxypropyl methylcellulose and sodiumcarboyxmethylcellulose, hydroxypropyl methylcellulose; a waterinsoluble, water swellable copolymer reduced by forming a dispersion offinely divided copolymer of maleic anhydride with styrene, ethylene,propylene, butylene or isobutylene cross-linked with from 0.001 to about0.5 moles of saturated cross-linking agent per mole of maleic anhydridein copolymer; water swellable polymers of N-vinyl lactams;polyoxyethylene-polyoxypropylene gel; polyoxybutylene-polyethylene blockcopolymer gel; carbo gum, polyacrylic gel; polyester gel; polyuria gel;polyether gel; polyamide gel; polyamide gel; polypeptide gel; polyamineacid gel; polycellulosic gel; polygum gel; initially drug hydrogels thatgenerally imbibe and absorb water which penetrates the glassy hydrogeland lowers its glass transition temperature; and the like.

Other osmopolymers include polymers that form hydrogels such asCarbopol® acidic carboxy polymers, a polymer of acrylic acidcross-linked with a polyallyl sucrose, also known ascarboxypolymethylene and carboxyvinyl polymer having a molecular weightof 250,000 to 4,000,000Cyanamer® polyacrylamides; cross-linked waterswellable indene-maleic anhydride polymers; Good-rite® polyacrylic acidhaving a molecular weight of 80,000 to 200,000; Polyox® polyethyleneoxide polymers having a molecular weight of 100,000 to 8,500,000 andhigher; starch graft copolymers; Aqua-Keeps® acrylate polymerpolysaccharides composed of condensed glucose units such as diestercross-linked polyglucan; and the like. Representative polymers that formhydrogels are known to the prior art in U.S. Pat. No. 3,865,108 issuedto Hartop; U.S. Pat. No. 4,002,173 issued to Manning; U.S. Pat. No.4,207,893 issued to Michaels; and in Handbook of common Polymers, byScott and Roff, published by the Chemical Rubber Company, Cleveland,Ohio. The amount of osmopolymer in the third or push osmotic compositionis about 0.01 to 99%. In a presently preferred operation arrangement,the osmopolymer composition comprising third layer 24 exhibits a lesserosmotic pressure than the osmotic pressure than second layer 22 andfirst layer 18. During operation of dosage form 10, fluid is imbibedinto dosage form 10 resulting in a greater viscosity of third layer 24than the viscosity of second layer 22 which exhibits a greater viscositythan first layer 18. The present invention provides a sequential osmoticpressure (π), and (N) viscosity gradient according to equation 4,wherein (1) denotes first layer 18, (2) denotes drug layer 22 and (3)denotes third layer 24. ##EQU4##

The third push layer 24 comprises additionally from 0 wt. % to 5 wt. %of a lubricant such as magnesium stearate, calcium stearate, potassiumstearate, lithium stearate, stearic acid and the like; from 0 wt. % to 3wt. % of a colorant such as red ferric oxide; from 0 wt. % to 40 wt. %of an osmotically effective compound used for the present purposecomprise magnesium sulfate, magnesium chloride, potassium sulfate,sodium sulfate, lithium sulfate, potassium acid phosphate, mannitol,urea, magnesium succinate, tartaric acid, carbohydrates such asraffinose, sucrose, glucose, sodium chloride, and the like; and from 0wt. % to 30 wt. % of a binder such as hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and the like. Thecomposition of all ingredients present in third layer 24 is equal to 100wt. %.

Dosage form 10, as seen in drawing FIG. 4, comprises at least onepassageway 13, or more than one passageway 13. The expression "at leastone passageway" includes aperture, orifice, bore, pore, porous elementthrough which the drug can be pumped, diffuse, travel or migrate, hollowfiber, capillary tube, porous overlay, porous insert, microporousmember, and the like. The expression also includes a material thaterodes or is leached from wall 12 in the fluid environment of use toproduce at least one passageway in dosage form 10. Representativematerial suitable for forming at least one passageway, or a multiplicityof passageways, includes an erodible poly(glycolic) acid or poly(lactic)acid member in the wall; a gelatinous filament; poly(vinyl alcohol);leachable materials such as fluid removable pore formingpolysaccharides, salts, or oxides, and the like. A passageway or aplurality of passageways can be formed by leaching a material such assorbitol, sucrose, lactose, fructose or the like, from the wall. Thepassageway can have any shape such as round, triangular, square,elliptical, and the like, for assisting in the metered released of drugfrom dosage form 10. Dosage form 10 can be constructed with one or morepassageways in spaced apart relation on one or more than a singlesurface of a dosage form. Passageways and equipment for forming passagesare disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899 by Theeuwes andHiguichi; in U.S. Pat. No. 4,063,064 by Saunders et al; and in U.S. Pat.No. 4,088,866 by Theeuwes et al. Osmotic passageways of controlled drugreleasing dimension, sized, shaped and adapted as a drug releasing poreformed by leaching to provide a drug-releasing pore of controlledosmotic release rate are disclosed in U.S. Pat. No. 4,200,098 by Ayerand Theeuwes; and in U.S. Pat. No. 4,285,987 by Ayer and Theeuwes. Indrawing FIG. 4, layer 18 is manufactured with increased thickness forincreasing the drug-free interval of dosage form 10.

Wall 12 of osmotic dosage form 10 can be formed in one technique usingthe air suspension procedure. This procedure consists in suspending andtumbling the compressed laminate in a current of air and wall formingcomposition until a wall is applied to the drug-forming compartment. Theair suspension procedure is well-suited for independently forming thewall. The air suspension procedure is described in U.S. Pat. No.2,799,241; J. Am. Pharm. Assoc., Vol. 48, pp 451 to 459, (1959); andibid, Vol. 49, pp 82 to 84, (1960). Osmotic dosage forms can also becoated with a wall-forming composition in a Wurster® air suspensioncoater, using methylene dichloride-methanol cosolvent, 80:20, wt:wt, oracetone-water cosolvent, 85:15 or 90:10 or 95:5 wt:wt using 2.5 to 5%solids. The Aeromatic® air suspension coater using a methylenedichloride-methanol cosolvent, 87:13, wt:wt, also can be used forapplying the wall. Other wall forming techniques such as pan coatingsystem, wall forming compositions are deposited by successive sprayingof the composition on the trilaminate compartment, accompanied bytumbling in a rotating pan. A pan coater is used to produce thickerwalls. A larger volume of solvent, such as methanol can be used in acosolvent to produce a thinner wall. Finally, the wall coatedcompartments are dried in a forced air oven at 30° C. to 50° C. for upto a week, or a humidity controlled oven at 50 R.H. and 50° C. up to 2to 5 days, to free the dosage form of solvent. Generally, the wallsformed by these techniques have a thickness of 2 to 20 mils with apresently preferred thickness of 4 to 10 mils.

Dosage for 10 of the invention is manufactured by standard manufacturingtechniques. For example, in one manufacture the beneficial drug andother ingredients comprising the drug layer facing the exit means areblended and pressed into a solid layer. The drug and other ingredientscan be blended also with a solvent and mixed into a solid or semisolidformed by conventional methods such as ball-milling, calendering,stirring or rollmilling and then pressed into a preselected shape. Thelayer possesses dimensions that correspond to the internal dimensions ofthe area the layer is to occupy in the dosage form and it also possessesdimensions corresponding to the second layer for forming a contactingarrangement therewith. Next, the osmopolymer, hydrogel or push layer, isplaced in contact with the drug layer. The osmopolymer layer ismanufactured using techniques for providing the drug layer. A delaylayer is manufactured using similar procedures. The layering of the druglayer, the osmopolymer layer, and the delay layer, can be fabricated byconventional press-layering techniques. Finally, the three-layercompartment forming members are surrounded and coated with an outerwall. A passageway is laser drilled through the wall to contact thedelay layer, with the dosage form optically oriented automatically bythe laser equipment for forming the passageway on the preselectedsurface.

In another manufacture, the dosage form is manufactured by the wetgranulation technique. In the wet granulation technique, for example,the drug and the ingredients comprising the drug layer are blended usingan organic solvent, such as isopropyl alcohol-ethylene dichloride 80:20v:v (volume:volume) as the granulation fluid. Other granulating fluidsuch as denatured alcohol 100% can be used for this purpose. Theingredients forming the drug layer are individually passed through a 40mesh screen and then thoroughly blended in a mixer. Next, otheringredients comprising the drug layer are dissolved in a portion of thegranulation fluid, such as the cosolvent described above. Then, thelatter prepared wet blend is slowly added to the drug blend withcontinual mixing in the blender. The granulating fluid is added until awet blend is produced, which wet mass then is forced through a 20 meshscreen onto oven trays. The blend is dried for 18 to 24 hours at 30° C.to 50° C. The dry granules are sized then with a 20 mesh screen. Next, alubricant is passed through an 80 mesh screen and added to the dryscreen granule blend. The granulation is put into milling jars and mixedon a jar mill for 1 to 15 minutes. The delay layer and the push layersare made by the same wet granulation techniques. The compositions arepressed into their individual layers in a Manesty® press-layer press.

Another manufacturing process that can be used for providing thecompartment-forming composition layers comprises blending the powderedingredients for each layer independently in a fluid bed granulator.After the powdered ingredients are dry blended in the granulator, agranulating fluid, for example, poly(vinyl-pyrrolidone) in water, or indenatured alcohol, or in 95:5 ethyl alcohol/water, or in blends ofethanol and water is sprayed onto the powders. Optionally, theingredients can be dissolved or suspended in the granulating fluid. Thecoated powders are then dried in a granulator. This process granulatesall the ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant such as stearic acid ormagnesium stearate is added to the granulator. The granules for eachseparate layer are pressed then in the manner described above.

The osmotic device of the invention is manufactured in anotherembodiment by mixing a drug with composition forming ingredients andpressing the composition into a solid lamina possessing dimensions thatcorrespond to the internal dimensions of the compartment. In anotherembodiment the drug and other drug composition-forming ingredients and asolvent are mixed into a solid, or a semisolid, by conventional methodssuch as ballmilling, calendering, stirring or rollmilling, and thenpressed into a preselected lamina forming shape. Next, a lamina of acomposition comprising an osmopolymer and an optional osmagent areplaced in contact with the lamina comprising the drug lamina. Then, alamina of a composition comprising a drug-free lamina is placed incontact with the other side of the drug lamina and the three laminacomprising the trilaminate surrounded with a semipermeable wall. Thelamination of the middle drug lamina, the first delay lamina and thethird lamina comprising the osmopolymer and optional osmagentcomposition can be accomplished by using a conventional layer tabletpress technique. The wall can be applied by molding, spraying or dippingthe pressed shapes into wall forming materials. Another and presentlypreferred technique that can be used for applying the wall is the airsuspension coating procedure. The procedure consists in suspending andtumbling the two layered laminate in current of air until the wallforming composition surrounds the laminate. The air suspension procedureis described in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Vol, 48,pp 451-459 (1979); and, ibid, Vol. 49, pp 82-84 (1960). Other standardmanufacturing procedures are described in Modern Plastics Encyclopedia,Vol. 46, pp 62-70 (1969); and in Pharmaceutical Science, by Remington,14th Ed., pp 1626-1979, (1970), published by Mack Publishing Co.,Easton, Pa.

Exemplary solvents suitable for manufacturing the wall, the laminatesand laminae include inert inorganic and organic solvents final laminatedwall. The solvents broadly include members selected for the groupconsisting of aqueous solvents, alcohols, ketones, esters, ethers,aliphatic hydrocarbons, halogenated solvents, cyclaliphatics, aromatics,heterocyclic solvents and mixtures thereof. Typical solvents includeacetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butylalcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane,n-heptane ethylene glycol monoethyl ether, ethylene glycol monoethylacetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane,tetrachoroethan, ethyl ether, isopropyl ether, cyclohexane,cyclo-octane, benzene, toluene, naphtha, tetrahydrofuran, diglyme,aqueous and nonaqueous mixtures thereof, such as acetone and water,acetone and methanol, acetone and ethyl alcohol, methylene dichlorideand methanol, and ethylene dichloride and methanol.

DETAILED DISCLOSURE OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and accompanying claims.

EXAMPLE 1

A dosage form adapted, designed and shaped as an osmotic drug deliverysystem is manufactured as follows: first 4,000 g of polyethylene oxidehaving a molecular weight of about 100,000 is mixed with 5,950 g ofsorbitol in a Hobart® mixer at slow speed for 20 minutes. Then, 4 litersof denatured ethanol is slowly added to the above mixer and the mixingcontinued for an additional 5 minutes to produce a wet granulation.Next, the wet granulation is dried at 31° C. in an oven for 16 hours,and after cooling to room temperature it is passed through a 20 meshscreen. Finally, 50 g of magnesium stearate is added to the granulationand all ingredients are mixed in a roller mill for 1 to 3 minutes, toyield a drug-free composition.

Next, 7,000 g of verapamil HCL, 2,500 g of polyethylene oxide, having amolecular weight of about 5,000,000 and 500 g of polyvinyl pyrrolidoneare mixed in a Hobart® mixer at slow speed for 30 minutes. Then, 3.6liters of anhydrous ethanol is added slowly to the above mixer and themixing continued for an additional 4 minutes to yield a wet granulation.Next, the wet granulation is passed through a 7 mesh screen in aFluid-Air® mill at 600 rpm, followed by drying the granules at 30° C. ina forced air oven for 18 hours. The dry granules next are passed througha 7 mesh screen in a Fluid-Air® mill jacketed with chilled water(4° C)at 550 rpm. Finally, 50 g of magnesium stearate is added to thegranulation and al the ingredients mixed in a V-blender for 3 minutes toyield a drug composition.

Next, an osmotic or push composition is prepared by passing separatelythrough a 40 mesh screen the following ingredients:8,470 g of sodiumcarboxymethyl cellulose with a molecular weight of 700,000, 940 g ofhydroxypropyl cellulose with a molecular weight of 60,000, 470 g ofsodium chloride and 100 g of ferric oxide. All of the screenedingredients are then thoroughly mixed in a mixer to yield a homogeneousmix. Then, with continuous mixing, 40 ml of denatured anhydrous ethanolare slowly added and mixing is continued for 2 more minutes to yield awet granulation. Next, the wet granulation is passed through a 20 meshscreen, dried at room temperature for 16 hours and passed again througha 20 mesh screen. Finally, 20 g of magnesium stearate is added togranulation and the ingredients mixed in a roller mill for 3 minutes toyield an osmotic composition.

A three-layered Manesty tablet press is used for forming the three-layerlaminate. The press is set with 7/16' diameter dies and standard concavepunches. First, 200 mg of the drug-free composition is added to the dieand tamped, then, 380 mg of the second or drug composition is added tothe die and tamped, and then, 120 mg of the third or osmotic compositionis added to the die and the three laminae are compressed at 3 toncompression pressure to yield the three laminae in contacting laminatedarrangement.

Next, the laminates are surrounded with a semipermeable wall. Thewall-forming composition comprises 70% cellulose acetate having anacetyl content of 39.8% and 30% hydroxypropylcellulose with a molecularweight of 60,000. The wall-forming composition is dissolved in methylenechloride:methanol (80:20 wt:wt) solvent to make a 4% solids solution.The wall-forming composition is sprayed onto and around the laminates inan Aeromatic Air® suspension Coater. Finally, the coated laminates aredried for 48 hours in a humidity oven set at 50% relative humidity and50° C. to evaporate the coating solvents. The coated wall surroundingthe laminate weighed 28 mg.

Next, two 40 mil exit ports are drilled on the drug-free or delay-layerside of the dosage form. Accompanying FIG. 6 depicts the release rateover time and FIG. 7 depicts the cumulative amount of drug releasedrelease after a drug-free interval.

EXAMPLE 2

Following the procedure of Example 1, an osmotic device is manufacturedcomprising a first or drug-free composition consisting of 92% sorbitol;2.5% polethylene oxide exhibiting a 5,000,000 molecular weight; 4%polyvinyl pyrrolidone; and 1.5% magnesium stearate. Accompanying FIG. 8depicts the release rate of the drug verapamil HCL over time andaccompanying FIG. 9 depicts the cumulative amount of drug released aftera drug-free period.

EXAMPLE 3

Following the procedure of Example 1, an osmotic device is manufacturedwith a drug composition comprising: 40% nicardipine; 58.5% polyethyleneoxide having a molecular weight of 300,000; 1% polyvinyl pyrrolidone;and 0.5% magnesium stearate. Following the procedure, the final osmoticdevice comprised a first drug-free layer weighing 250 mg, a second ordrug layer weighing 100 mg, and a third osmotic layer weighing 250 mg.The wall of the osmotic device comprises 95% cellulose acetate having a39.8% acetyl content and 5% polyethylene glycol having a 4,000 molecularweight, and a 3 mil thickness. Accompanying FIG. 10 depicts from theosmotic device the release rate of nicardipine over time and FIG. 11depicts the cumulative amount of drug release following a drug-freeperiod.

EXAMPLE 4

An osmotic delivery device manufactured in the appearance of an osmotictablet shaped, sized and adapted for oral admittance into thegastrointestinal tract is made as follows: first, a drug-freecomposition is prepared by screening through a 40 mesh screening 205 gof polyethylene oxide having a 150,000 molecular weight, and screeningthrough a 40 mesh screen 315 g of mannitol and fructose followed byblending the two ingredients in a blender, for 15 minutes. Next, 200 mlof ethanol is added to the blender and the mixing continued for 5minutes, to yield a wet granulation. The wet granulation next id driedat 37° C. in an air oven for 12 hours, and the dried granulation passedthrough a 20 mesh screen. Finally, 5 g of stearic acid is added to thegranulation and all the ingredients thoroughly blended in a roller millfor 4 minutes, to yield a drug-free composition.

Next, a drug composition is prepared as follows: first, 105 g ofpolyethylene oxide having an approximate molecular weight of 300,000 isscreened through a 40 mesh stainless steel screen, then 200 g ofdiltiazem HCL is screened through the 40 mesh screen, next 25 g ofhydroxypropylcellulose is passed through the screen, 2 g of potassiumchloride is passed through the 40 mesh screen and finally 5 g ofsorbitol is passed through the 40 mesh screen. Next, all the screenedingredients are added to the bowl of a blender and the ingredients dryblended for 15 to 20 minutes to produce a homogeneous blend. Then, agranulation fluid is prepared comprising 250 ml of ethanol and 250 ml ofisopropyl alcohol, and the granulating fluid is added to the blendingbowl; first 50 ml of the granulating fluid is sprayed into the bowl withconstant blending, then 1000 ml of the granulation fluid is added slowlyto the bowl and the wet mass blended for another 15 to 20 minutes. Then,the wet granules are passed through a 16 mesh screen and dried at roomtemperature for 24 hours. Next, 10 g of calcium stearate is added to thedry granules, and all the ingredients roll mixed for 20 to 30 minutes ona standard two-roll mill.

Next, a third or osmotic composition is prepared as follows: first, 170g of poly(ethylene oxide) having a molecular weight of 5,000,000 isscreened through a 40 mesh screen, then 10 g of sodium chloride ispassed through the 40 mesh screen, and the ingredients added to a mixingbowl and blended for 10 to 15 minutes. Then, a granulation fluid isprepared by mixing 350 ml of ethanol and 150 ml of isopropyl alcohol,and the granulation fluid added to the blending bowl in two steps.First, 50 ml of the granulation fluid is sprayed into the bowl withconstant blending; then 110 ml of the granulation fluid is slowly addedto the bowl and the wet blend mixed for 15 to 20 minutes to ahomogeneous blend. Then, the wet blend is passed through a 16 meshscreen, spread on a stainless steel tray and dried at room temperatureof 22.5° C. for 24 hours. The dried blend is passed through a 16 meshscreen, then roll milled with 2 g of magnesium stearate on a two-rollmill for 20 to 30 minutes.

A number of three-layer dry cores are prepared by pressing the threecompositions on a Manesty three-layer press. The drug-free compositionis fed into the cavity mold of the press and compressed into a solidlayer, then, the drug composition is fed into the cavity mold of thepress and compressed into a solid layer, then the third or osmoticcomposition is fed into the cavity overlaying the compressed two layersand pressed into a solid layer to form a three-layered drug core.

The drug cores next are coated with a semipermeable wall formingcomposition comprising 35 g of cellulose acetate having an acetylcontent of 39.8%, 25 g of cellulose acetate having a 32% acetyl content,and 10 g of hydroxypropyl-cellulose, having a molecular weight of200,000 in a solvent comprising 1960 ml of methylene chloride and 820 mlof methanol. The drug cores are coated with the semipermeable wallforming composition until the wall surrounds the drug core. A Wurster®air suspension coater is used to form the semipermeable wall. The coatedcores are then spread on a tray and the solvent evaporated in acirculating air oven at 50° C. for 65 hours. After cooling to roomtemperature, three 0.85 mm diameter passageways are laser drilledthrough the semipermeable wall connecting the exterior of the osmoticdevice with the drug-free composition. The dosage form, after adrug-free interval delivers drug for and extended period.

EXAMPLE 5

An osmotic dosage form is prepared according to Example 4 foradministering after a delayed interval a therapeutically effectiveamount of a member selected from the group consisting of nimodipine,nitredipine, nisoldipine, felodipine, lidoflazine, trapemil, isradipine,gallopamil, amlodipine, mioflazine, nilvadipine, and caroverine,

EXAMPLE 6

An osmotic dosage form is prepared according to claim 4 for the delayedadministration of a therapeutically effective amount of a vasodilatorselected from the group consisting of amyl nitrate, glyceryl trinitrate,octyl nitrite, sodium nitrite, erythrityl tetranitrate, isosorbidedinitrate, mannitol hexanitrate, pentaerythritol tetranitrate,pentritol, triethanolamine trinitrate, and trolnitrate phosphate.

EXAMPLE 7

A dosage form sized, shaped and adapted as an osmotic device for oraladministration into the gastrointestinal tract of a human is made asfollows: first, a drug-free composition is prepared by individuallyscreening through a 40 mesh screen potassium chloride crystals,mannitol, cross-linked polyvinyl pyrrolidone and calcium stearate. Thepotassium chloride crystals were dried in an oven for 4 hours at 50° C.prior to the granulation to remove moisture. Next, noncross-linkedpolyvinyl pyrrolidone was dissolved in denatured alcohol to prepare abinder solution. The composition forming excipients were mixed next in astandard Hobart® mixer to produce a consistent wet mixture. The wet massof wet granules were passed through a 16 mesh screen, spread on a flatpan and dried in a 50° C. forced air ambient humidity for approximately24 hours to remove the granulation ethanol solvent. The dried granuleswere passed through a 16 mesh screen, and blended with calcium stearatein a blender for 2 minutes to yield a drug-free composition.

A drug composition comprising guanabenz acetate for the treatment ofhypertension is prepared by screening it through a 60 mesh screen,followed by screening microcrystalline cellulose, polyvinyl pyrrolidoneand mannitol independently through a 40 mesh screen. Next, all theingredients are blended for about 20 minutes to produce a homogeneousblend. Next, silicon dioxide is screened through an 80 mesh screen, andthen magnesium stearate is screened through the 80 mesh screen. Thescreened silicon dioxide and magnesium stearate are added to the blendand all the ingredients blended for 5 minutes.

Next, a push layer comprising phenylene oxide having a 5,000,000molecular weight, hydroxypropylmethylcellulose, ferric oxide and ethylalcohol are blended to a wet granulation. The wet granulation isscreened through a 16 mesh screen and dried in at 50° C. in an ovenovernight. The dried granules are screened through a 16 mesh screen.Then, magnesium stearate is screened and added to the dried granulation.Finally, all the ingredients are blended for 5 minutes to yield ahomogeneous blend.

The dosage form comprising the first drug-free layer, the drug layer andthe push layer is prepared in a Carver® press using a 1/2 inch, standardconcave die. First, the drug-free layer is placed in the die and pinchedto compress the granulation. Next, the middle-forming drug layer isplaced on top of the drug-free layer and compressed to form a continuousmiddle layer. Then, the third-forming layer is placed on top of themiddle layer and compressed with a force of 2.5 tons of force.

The three-layer laminate is surrounded with a wall in an Aeromatic®Coater. The wall-forming composition comprises 51 g of cellulose acetatehaving an acetyl content of 43.5%, 9 g of hydroxypropylcellulose and acosolvent containing 1,170 ml of methylene chloride and 490 ml ofmethanol. During the wall-forming process, 960 ml of wall-formingsolution is used to apply a 12.3 mg wall on each three-layered dosageform. The dosage forms are dried in an oven overnight at 50° C. to yielda final dry wall of 10.4 mg per dosage form. A single 15 mil (0.325 mm)passageway is drilled through the wall connecting the exterior of thedosage form with the first layer. In an automatic laser drillingtechnique, the first layer is selected by photo examination apparatus ofthe layer. The dosage form comprises 4 mg of guanabenz acetate.

Next, an exterior, quick-releasing guanabenz acetate lamina and otherexterior forming lamina ingredients comprising hydroxypropyl-cellulose,polyethylene oxide and a small portion of hydroxypropyl-methylcelluloseare added and blended in a moving current of air containing distilledwater and magnesium stearate, to yield an immediate release layer thatis compressed around the dosage form. Finally, the lamina wall coatedcompartments are dried to yield the final dosage form. The exteriorimmediate release layer comprises 4 mg of guanabenz acetate. The dosageform provided by this example is indicated for twice a day (b.i.d.)therapy. The dosage form on entering the gastrointestinal tract deliversthe guanabenz acetate immediately, the first dose, and several hourslater commences to delivery the guanabenz acetate, the second dose. Theimmediate first dose provides antihypertensive action that reaches atherapeutic peak followed by a drug-free interval and then the seconddose that provides antihypertensive action that reaches its therapeuticpeak to enable the blood pressure to approach baseline values. Thedosage form accordingly provides a favorable therapeutic index, withconvenient, as a compliance-enhancing b.i.d. dosage form.

DESCRIPTION OF METHOD OF PERFORMING THE INVENTION

A presently preferred embodiment of the invention pertains to a methodfor delaying the delivery of a drug to the gastrointestinal tract of ahuman followed by delivery of drug at a controlled rate andcontinuously, which method comprises the steps of: (A) admitting orallyinto the human's gastrointestinal tract a dispensing device comprising:(1) a wall comprising means for imbibing an external aqueous fluidthrough the wall into the dispensing device, which wall surrounds andforms an internal compartment; (2) a first composition in thecompartment, said compartment comprising a drug-free composition fordelaying the delivery of the drug from inside the dispensing device forup to 61/2 hours from the compartment; (3) a second composition in thecompartment comprising a dosage unit amount of drug; (4) a thirdcomposition in the compartment for pushing the drug from thecompartment; (5) exit means in the wall for delivering the drug from thedevice; (B) imbibing fluid through the wall into the compartment forcausing the first composition to be delivered and concomitantly delaythe delivery of drug from the compartment; (C) imbibing fluid into thethird composition to expand and push the drug from the device; and (D)delivering the beneficial drug from the compartment by the thirdcomposition expanding continuously thereby causing the drug to bedispensed through the exit means at a therapeutically effective amountat a controlled rate over a period of time to the human. The dispensingdevice, in an embodiment of the invention comprises an instant releaseexterior dosage amount of drug for providing b.i.d. drug delivery.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made hererin, in accordance with the inventive principles disclosed,without departing from the scope of the invention.

We claim:
 1. A dosage form for administering a dose of a drug twice aday from a single dosage form, which dosage form comprises:(1) acompartment; (2) a wall that surrounds and forms the compartment, saidwall comprising a composition that is permeable to the passage of fluid;(3) a first composition in the compartment, said first compositiondrug-free for producing a drug-free interval prior to the administrationof drug from the compartment; (4) a second composition in thecompartment comprising a dose amount of a drug for producing atherapeutic effect; (5) a third composition in the compartment thatexpands in the presence of fluid that enters the device; (6) exit meansin the wall for connecting the exterior of the dosage form with thecompartment; and, (7) a substantially immediate release dose amount ofdrug on the exterior surface of the wall.
 2. A dosage form foradministering a first dose and a second dose of drug, said dosage formcomprising:(1) a compartment; (2) a wall that surrounds and forms thecompartment, said wall comprising a composition that is permeable to thepassage of fluid; (3) a first dose of drug for producing a therapeuticeffect on the exterior surface of the wall; (4) a first composition inthe compartment, said first composition substantially drug-free forproducing a drug-free interval prior to the administration of drug fromthe compartment; (5) a second composition in the compartment comprisinga second dose amount of a drug for producing a therapeutic effect; (6) athird composition in the compartment that expands in the presence offluid that enters the device; and, (7) exit means in the wall forconnecting the exterior of the dosage form with the compartment.
 3. Thedosage form for administering the drug according to claim 2, wherein thedrug is a member selected from the group consisting of verapamil,nimodipine, nitredipine, nisoldipine, nicardipine, felodipine,diltiazem, lidoflazine, tiapamil, guanabenz, isradipine, gallopamil,amlodipine, mioflazine, and caroverene.
 4. The dosage form foradministering the drug according to claim 2, wherein the drug is amember selected from the group consisting of amyl nitrate, glyceryltrinitrate, octyl nitrite, sodium nitrite, erythrityl tetranitrate,isosorbide dinitrate, mannitol hexanitrate, pentaerythritoltetranitrate, pentritol, triethanolamine trinitrate, and trolnitratephosphate.
 5. The dosage form for administering the drug according toclaim 2, wherein the exit means is a pore.
 6. A dosage formcomprising:(1) a wall that surrounds: (2) a first composition, whichfirst composition is a means for delaying the delivery of a drug fromthe dosage form; (3) a second composition comprising 25 nanograms to 1.5grams of the drug verapamil; (4) a third composition that expands in thepresence of fluid that enters the dosage form causing the thirdcomposition to increase in physical dimensions and push against thefirst and second composition, whereby verapamil is delivered from thedosage form; and, (5) exit means in the wall connecting the exteriorwith the interior of the dosage form for delivering the verapamil fromthe dosage form.
 7. A therapeutic composition comprising 0.05 ng to 1.5g of verapamil and a member selected from the group consisting ofpoly(vinyl pyrrolidone), poly(alkylene oxide) and a poly(cellulose),which therapeutic composition can be delivered from an osmotic dosageform for an antianginal, antiarrhythmic, and antihypertensivetherapeutic effect in a patient in need of verapamil therapy.
 8. Atherapeutic composition according to claim 7, wherein verapamil is inthe therapeutic composition as a pharmaceutically acceptable salt.